Classifications

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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• Emulsions for the topical treatment of dermal infections are provided.
• the invention relates to emulsions for the topical treatment of dermal infections and mucosal infections, in particular of urogenital infections.
• vaginal infections often occur for various reasons, caused for example by the almost ubiquitous fungi of the species Candida, which change easily from commensal to pathogen, on the other hand by bacteria such as Gardnerella vaginalis, Mobiluncus or Prevotella spp., As well as by streptococci or Staphylococci or for example, by typical gut germs, such as Enterobacter, E. coli and / or about Klebsiella pneumoniae, which alone because of the spatial proximity of the body openings can easily get into the vagina by smear infection.
• asymptomatic Fehlbesiedelache result. If certain threshold levels of foreign germs are exceeded and infection-promoting factors are added, ultimately a virulent infectious event breaks out.
• US 2007/292355 A1 relates to anti-infective foamable compositions containing an anti-infective agent and a keratolytic agent.
• the compositions are used in the treatment of fungal, bacterial or viral infections.
• AT 11 910 Ul relates to a composition comprising chlorhexidine, bisphosphonate, a non-steroidal anti-inflammatory drug (NSAID) and an immunomodulator (tetracycline), inter alia, for the treatment or prevention of oral, mucosal or dermal infections or inflammations.
• NSAID non-steroidal anti-inflammatory drug
• immunomodulator tetracycline
• DE 10 2008 034944 A1 relates to honey-based microemulsions which, together with other active substances, including NSAIDs, can be introduced into the body by topical application into the skin or orally, nasally or percutaneously.
• WO 2011/060083 A1 relates to methods for the prevention or treatment of external ear infections with compositions containing antibiotics, Antifungals, antiparasitics, antiviral agents, NSAIDs, analgesics, anesthetics and / or steroids.
• WO 02/078648 A2 relates to topical pharmaceutical compositions containing an antimycotic, e.g. Terbinafine, and another drug, e.g. Diclofenac or indomethacin.
• an antimycotic e.g. Terbinafine
• another drug e.g. Diclofenac or indomethacin.
• the present invention relates to medicaments for the topical treatment of bacterial dysbiosis and manifest infectious diseases, including mixed infections with fungi and other microorganisms. Accordingly, the present invention relates to an emulsion for the topical treatment of dermal infections and mucosal infections, in particular of urogenital infectious diseases, in particular for use in the topical treatment of urogenital bacterial infections, which is characterized in that an antimicrobial agent and an antiadhesive agent, preferably an NSAID , be used in combination.
• an antimicrobial agent and an antiadhesive agent preferably an NSAID
• vaginosis and vaginitis Bacterial defecation of the vagina to symptomatic vaginal infections are common.
• the transition from asymptomatic non-inflammatory colonization to symptomatic disease is further defined by the terms vaginosis and vaginitis.
• aerobic vaginosis / vaginitis and anaerobic vaginosis / vaginitis provide a more accurate determination of the causative agents.
• a problem common to all vaginal infections, regardless of the pathogen organism, is the formation of so-called biofilms.
• biofilms The mucosal surfaces
• the affected organs vagina, urethra, bladder, penis
• Bacterial dysbiosis and infections can be effectively treated by a drug combination consisting of an antimicrobial drug with an anti-adhesive agent. Adhesion inhibition breaks up the biofilm and removes it from the epithelium of the host. At the same time, all germs contained therein are released and made accessible to direct antimicrobial treatment.
• One of the most widely used classes of drugs among the anti-adhesive agents is the non-steroidal anti-inflammatory drugs (NSAIDs), These have, in addition to the anti-adhesive effect on an anti-inflammatory effect and immediate pain inhibition, which is in view of the often associated with pain vaginal infections another particular advantage. Since chronic infections are also associated with chronic inflammation, the anti-inflammatory effect, especially in chronic infections is of particular importance.
• NSAID for the disruption of the biofilm is the presence of the NSAID in the described concentrations and conditions in an emulsion in the composition described and in the proportions described.
• Particularly suitable NSAIDs according to the invention are diclofenac, bufexamac, ibuprofen, dexibuprofen, flurbiprofen, ketoprofen, piroxicam, meloxicam, lornoxicam, flufenamic acid, mefenamic acid, indomethacin or naproxen.
• the usual concentration in which diclofenac is used topically is in the range of 1 to 2% (10 mg / or 20 mg / g). In the context of the present invention, it is preferred that diclofenac be used in an amount of 0.1% to 0.5% (1-5 mg per g of cream), preferably of 0.2.%. up to 0.4%.
• the usual concentration in which ibuprofen is used topically is 5% (50 mg / g cream / gel). In the context of the invention, ibuprofen is used in a preferred amount of from 0.5 to 2.5% (5-25 mg per g cream), preferably from 1 to 2%. Further examples of preferred NSAIDs and their preferred amounts (“Inventive Concentration”) can be seen from Table A.
• the emulsion is in the form of an ointment or cream.
• it is an aqueous phase-oil phase emulsion containing an antimicrobial agent and an NSAID, characterized in that (a) the NSAID is present in the aqueous phase in a concentration range of one-half to one-tenth of that for this Active ingredients in approved usual dermal formulations apply to (b) the weight ratio of water to oil phase in this emulsion is between 2.0 and 2.7, and (c) the pH of the emulsion is not below 6 5 and not more than 8.5 preferably in the range 7.0 to 8.0, preferably for the treatment of urogenital infectious diseases, in particular for use in the topical treatment of vaginal infections and cystitis of the female and for local partner treatment (Glans penis, Initial third of the urethra).
• the preparations according to the invention in addition to the optimized pharmacokinetics by the attack directly at the site of infection, also show optimal pharmacodynamics.
• This not only allows a particularly good efficacy of the antimicrobial drug, but also the interaction with the NSAID significantly improved by a low concentration of NSAID nevertheless sufficient effectiveness is ensured without the side effects (irritation, burning, etc.) to have to accept.
• this leads to the fact that non-usable combinations of antimicrobial drugs and NSAIDs with the teachings of the present invention can be made accessible to the patients beforehand for these side-effects reasons, and these patients can now be supplied with successful therapy.
• the concentration of the NSAID in the aqueous phase is of crucial importance for an optimal pharmacodynamic effect.
• the availability of the incorporated NSAID is achieved by the interaction of the manufacturing process, the water / oil ratio, and the pH, which ensures the predominant presence of the NSAID in its salt form.
• Semi-solid emulsions oil in water or water in oil
• the viscosity of the emulsions is strongly determined by the water to oil ratio.
• the ratio of water to oil is of particular importance. With a higher proportion of fatty components, the development of effectiveness is hindered. On the other hand, it comes with a lower fat content to a stronger irritant effect.
• medicaments according to the present invention require the safe retention of the active ingredient, in particular the NSAID component at the site of action, in order to achieve the desired therapeutic effect. Therefore, in the drug, the ratio of the oil phase containing the antimycotic to the water phase in which the NSAID is located is in a relatively narrow range. Thus, if the viscosity is further reduced by increasing the level of the aqueous phase, uncontrolled leakage from the vaginal discharge is expected. Liquid emulsions or gels with high water content or with low viscosity are to be excluded as dosage forms for vaginal application according to the present invention.
• the water: oil ratio should not exceed the value of 2.7. Above this range, the active agent is washed out too quickly with the vaginal secretions, whereby there is insufficient time to unfold the adhesion-promoting effect on the outer layer of the vaginal epithelium to which the pathogen adheres.
• the excessively high water: oil ratio very quickly flushed out active ingredient may at best cause as a side effect also a irritating effect.
• the NSAIDs according to the invention be in salt form (or ionic form), both during incorporation and during use. Therefore, their incorporation into the formulation is important.
• the NSAID is typically incorporated into the aqueous phase prior to the preparation of the emulsion by the method of the invention.
• the solid salt of the NSAID can be incorporated in finely crystalline or micronized form, or as a hydrogel in the (largely) finished emulsion.
• NSAIDs are weak acids with a pKa of 4-5 (diclofenac 4.15, ibuprofen 4.91, mefenamic acid 4.2, indomethacin 4.5, naproxen 4.2). Accordingly, they are already present in the weakly acidic environment partly in free form and are thus extracted into the oil phase, which can lead to a reduced effect or loss of activity.
• the pH of an emulsion influences the basic physiological compatibility. Therefore, relatively narrow limits are also set with regard to the pH of the formulation.
• the (aqueous phase of the emulsion) has a pH in the range of 6.5 to 8.5, preferably 7-8.
• antibiotics or antiseptics are preferably used as antimicrobial agents.
• vaginal biofilms Among the bacterial microorganisms found in the vaginal biofilms are typical mostly facultative anaerobic intestinal bacteria such as Enterobacter, E. coli, Klebsiella pneumoniae and enterococci, but also ureaplasmas and mycoplasmas, and Gardnerella vaginalis, Prevotella spp. and Mobiluncus a special role.
• facultative anaerobic intestinal bacteria such as Enterobacter, E. coli, Klebsiella pneumoniae and enterococci, but also ureaplasmas and mycoplasmas, and Gardnerella vaginalis, Prevotella spp. and Mobiluncus a special role.
• Preferred antibiotics in the present invention which are also particularly suitable for the treatment of these germs, are phosphomycin, clindamycin, metronidazole, nitrofurantoin, nitrofurazone, nitrofurantoin, nifuratel, nifuroxacin, nitroxoline, trimethoprim, sulfadiazine, cotrimoxazole.
• Antiseptics can affect both non-bacterial microorganisms such as trichomonads and bacteria. At higher concentrations antiseptics exert an antibacterial effect and are suitable alone or together with an antibiotic for combination with an anti-adhesive agent according to the invention.
• the antimicrobial effect of the antiseptics is based primarily on the disruption of the integrity of the plasma membrane. Because of the basically same structure of the membrane of the endothelial cells, these agents have an inherent potential for inflammatory excitation. Since this potential is suppressed by NSAID, the combination preparations of antiseptics according to the invention offer a very special therapeutic advantage.
• Preferred antiseptics are quaternary ammonium salts, such as benzalkonium chloride, and dequalinium chloride, as well as phenoxyethanol. Preferred concentrations are at least 0.2 weight percent for benzalkonium chloride, at least 0.2 weight percent for dequalinium chloride, and at least 2 weight percent for phenoxyethanol.
• the terms "antimicrobial agent”, “antibacterial agent”, “antibiotics”, “antiseptics”, etc. are to be understood as meaning substances which are regarded as such active ingredients in conventional pharmaceutical use.
• composition of the drug combinations according to the invention is particularly suitable in the combinations described for the treatment of even complex chronic vaginal inflammation.
• the emulsions according to the invention are suitable for use on mucous membranes, in particular of urogenital infections.
• compositions which have a high content of mucous membrane damaging substances such as ethanol or isopropanol. It is therefore preferred that the emulsion according to the invention does not contain more than 10% of ethanol. It is also preferred that the emulsion of the invention does not contain more than 20% isopropanol. Since keratinized layers in mucous membranes, eg in the genitourinary area, do not occur, a keratoytic effect is not he wishes. For this reason, the strongly acidic, keratinolytic salicylic acid is not an NSAID according to the invention.
• Emulsions according to the present invention are also suitable for the treatment of urogenital mucosal disorders of the male on the glans penis and in the urethra.
• Bladder infections are common. They are mostly caused by bacterial infection. The bladder is poorly accessible for topical treatment. However, since the woman's urethra is located in the anterior vaginal entrance, the most common route of infection is from the vagina into the urethra. In addition, in urological and gynecological practice often complaints are seen, which can be attributed to an isolated inflammation of the urethra. The vagina thus becomes the primary germ reservoir for urethral and bladder infections. Although support for the antibiotic treatment of acute bladder infections can be achieved by the oral administration of adhesion-inhibiting plant extracts, which adhere to the bladder wall, the rehabilitation of the vaginal flora, which is usually affected by the infection, is the basic prerequisite for a sustainable healing. This can be achieved with the medicaments according to the invention. For this reason, drugs according to the present invention are effective cystitis therapeutics, both alone and in combination with bladder-only drugs.
• the antifungal agent is preferably a drug from the group of nystatin, ciclopirox or ciclopiroxolamine, or one of the group of azoles (imidazoles, triazoles, tetraazoles) such as clotrimazole, fluconazole, miconazole, itraconazole, tioconazole, voriconazole, bifonazole, econazole, isoconazole, fenticonazole , Sertaconazole, ketoconazole, posaconazole, quileconazole, otesconazole (VT-1161), ibrexafungerp (SCY-078).
• azoles imidazoles, triazoles, tetraazoles
• Medicaments according to the present invention have been developed primarily for the therapy of vaginosis and bladder infections.
• the invention therefore relates to Application of the emulsions according to the invention in the topical treatment of infectious diseases, in particular for use in the topical treatment of urogenital infections.
• the infectious disease is preferably a microbial (in particular a bacterial) urogenital infection, in particular a microbial (in particular a bacterial) urogenital infection of the woman.
• the infectious disease is a mixed vaginal infection by Candida albicans and bacteria such as Enterobacter, E. coli, Klebsiella pneumoniae, Gardnerella vaginalis, Prevotella spp.
• the infectious disease is an asymptomatic or symptomatic bacterial vaginosis or an asymptomatic or symptomatic dysbiosis of the glans penis and / or the male urethra.
• Both acne and genetic hair loss are associated with the male sex hormone testosterone.
• the contribution of this hormone to the pathogenetic process is primarily in the activation of sebaceous glands in the skin and in the hair follicles.
• the accumulated sebum is subsequently an ideal substrate for both a bacterial infection, especially with propionibacteria or with the fungi Candida and Malassezia. While Malassezia is mainly associated with the pityriasis versicolor, acne Propionibacterium acnis is in the foreground. Both are involved in hair loss.
• the large amount of sebum that accumulates in the hair follicles is an ideal substrate for biofilm formation.
• the same criteria apply to this biofilm as to biofilms that form in the vagina.
• the biofilm must first be broken open and its adhesion to the epithelium dissolved, so that subsequently the anti-infective agent can exert its effect.
• the emulsions according to the present invention are also very suitable for the treatment of skin diseases, especially pityriasis versicolor, acne and hair loss. Since the dermal applications can affect a much larger and clearly less circumscribed area than vaginal infections, special emulsions can be used in these cases. In particular, shampoos and acne creams, acne sticks or acne solutions are suitable for treating hair loss.
• sorbitan monostearate, polysorbate 60, cetyl palmitate, 2-octyldodecanol and cetostearyl alcohol are melted at a temperature of 70-75 ° C.
• Clindamycin (and optionally clotrimazole) and then phenoxyethanol are added to the clear melt with stirring at a temperature of 60 ° C. to 70 ° C.
• diclofenac sodium is dissolved in purified water with heating.
• the aqueous solution is added with stirring to the oil phase and homogenized. With slow cooling, with further homogenization of the resulting w / o emulsion, a phase reversal occurs, resulting in a hydrophilic, homogeneous cream.
• Emulsions containing phenoxyethanol as an antibacterial agent are provided.
• Gyn.U . mucous membrane bland, normal vaginal flora, lactobacilli flora.
• Gynecological examination Mucosa strongly reddened, fluid secretion, slightly greenish.
• Secretion smear native abundant biofilm plaques on thick fungal hyphae, leukocytes +++, hardly any lactobacilli, intermediary flora.
• Gyn.U . mucosa bland, lactobacilli flora
• Case example 31-year-old female patient (FJ), for about 3 years almost monthly premenstrual symptoms, each about 1 week to 10 days, due to recurrent fungal infections. For 1 week additionally vaginal secretions thin and foul-smelling. Burning and itching in the introitus.
• Gyn.U mucous membrane slightly reddened, fluid secretion, odor.
• Secretion smear native bacterial vaginosis (RG III), additionally fungal hyphae, abundant leucocytes.
• Gyn.U Mucosa strongly reddened, vaginal fluid thin and foul-smelling.
• Secretion smear native reichl. Clue cells, leucocytes +++, Bacterial vaginosis (RG III) Therapy: F4 for 1 week, 0-0-1 vaginally applied, then Hylept Vagilact. Check-up after 2 years: free of symptoms after the previous therapy, once very light
• Gyn.U pressure pain over bladder; Mucous membrane atrophic, bleeding on contact,
• Cervix atrophy soldered, opened with Cervixbrush, secretion: atrophy, aerobic mixed flora (RGIII), abundant leucocytes.
• Gyn.U mucosa bland, no DS over bladder and urethra; Secretion smear native: starting from normal vaginal flora (RG I), no leukocytes.
• Gynecological examination pressure pain via bladder; Vaginal mucosa in appearance rather inconspicuous, pronounced cervicitis with about 1 cm measuring bloody erosion around the cervix, secretion / native preparation: bacterial vaginosis, mass leukocytes, these are occupied with bacteria, isolated Lactobacilli, hyphae ++.
• Microbial smear - secretory culture massive E. coli.
• Gyn.U mucous membrane bland, no pressure pain on bladder and urethra
• Secretion smear native normal vaginal flora (RG I), no leukocytes.
• the individual portions of the water and the oil phase are summed up as shown in the table. Since emulsifiers, e.g. Sorbitan monostearate and polysorbate 60, at the interfaces between the two phases, they are neither the water nor the oil phase attributable.
• emulsifiers e.g. Sorbitan monostearate and polysorbate 60
• the weight ratio of water to oil phase could be included without consideration the substances dissolved in the phases (clotrimazole, diclofenac-Na, benzyl alcohol, cetylstearyl alcohol) are calculated.
• this calculation method only water and propylene glycol of the water phase, and cetyl palmitate, 2-octyldodecanol and cetystearyl alcohol of the oil phase would be attributed in Tab.
• the water-oil ratios 2.7, 3.1, 2.4, 2.4, 2.0, 1.7 given in Table 3 would, according to this calculation, be 2.9, 3.4, 2.6 , 2,6, 2,1, 1,8.
• the range of 2.0 to 2.7 according to the invention would correspond to a range of 2.1 to 2.9 in this calculation.
• Clotrimazole and NSAID emulsions were used to investigate the influence of pH on the clinical efficacy of the NSAID.
• Emulsions with various concentrations of diclofenac Na were prepared and tested for clinical efficacy.
• the invention relates to the following preferred embodiments:
• An emulsion for the topical treatment of dermal infections and mucosal infections, in particular of urogenital infectious diseases characterized in that an antimicrobial agent and an antiadhesive agent, preferably an NSAID, are used in combination.
• An emulsion according to embodiment 1 or 2 preferably in the form of an ointment or a cream, having an aqueous phase and an oil phase containing an antimicrobial agent and an NSAID, characterized in that (a) the NSAID in the aqueous phase in a Concentration range which corresponds to one-half to one-tenth of the concentration customary for these active ingredients in approved dermal formulations, (b) the weight ratio of water to oil phase in this emulsion is between 2.0 and 2.7, and ( c) the pH of the emulsion is not less than 6.5 and not more than 8.5, preferably in the range 7.0 to 8, preferably for the treatment of urogenital infectious diseases, in particular for use in the topical treatment of vaginal infections and bladder infections the woman as well as local partner treatment (glans penis, initial third of the urethra).
• An emulsion according to embodiment 1 or 2 preferably in the form of an ointment, cream, shampoo, solution or stick, having an aqueous phase and an oil phase containing an antimicrobial agent and an NSAID, characterized in that (a) the NSAID is present in the aqueous phase in a concentration range which at the cutaneous application at most the usual concentration, when applied to mucous membranes of half to one tenth of the usual concentration for these active ingredients and (b) the pH of the emulsion is not below the 5.5 and not more than 8.5, preferably for the topical treatment of dermal infections, in particular for use in the topical treatment of acne, alopecia, pytiriasis versicolor and atopic dermatitis.
• An emulsion according to any of embodiments 1 to 5 characterized in that the antimicrobial agent is an antibiotic.
• the antifungal agent is nystatin, ciclopirox or ciclopiroxolamine, or an antifungal from the group of the azoles, preferably clotrimazole, fluconazole, miconazole, itraconazole, tioconazole, voriconazole, bif
• An emulsion according to any one of embodiments 1 to 10 characterized in that the NSAID is diclofenac and this is contained in a concentration range of 0.2-0.4% by weight of the emulsion.
• An emulsion according to any of embodiments 1 to 12 for use in the topical treatment of infectious diseases, in particular for use in the topical treatment of dermal and urogenital infectious diseases.
• Emulsion for use according to embodiment 13 or 14 characterized in that the infectious disease is a microbial urogenital infection, in particular a microbial urogenital infection of the woman.
• Emulsion according to embodiment 20 characterized in that the emulsion is processed into an acne stick or an Anke solution.
• Emulsion preferably shampoos according to any of embodiments 1 to 12 for the treatment of hair loss.
• NSAID in the preparation of the emulsion, the NSAID is introduced via the aqueous phase

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